This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Research in the Keating lab aims to understand determinants of interaction specificity among human Bcl-2 family proteins. The Bcl-2 proteins regulate apoptotis and have emerged as important anti-cancer drug targets. We are studying the binding of short alpha-helical peptides derived from the BH3 region of pro-apoptotic Bcl-2 proteins to anti-apoptotic family members. We carry out binding studies and structural studies and combine these with computational methods to obtain a better understanding of how sequence determines interaction specificity. X-ray crystallographic studies are a key component of this work, as structure provides insights into how the receptor proteins can adjust to bind a range of different ligands. Because new structural snapshots can provide opportunities for peptide or small-molecule drug design, these studies have implications for the development of new therapeutics and diagnotics.